Lupane derivatives from Lophopetalum wallichii with farnesyl protein transferase inhibitory activity

• Main Authors: Sonja Sturm, Roberto R. Gil, Hee Byung Chai, Olipa D. Ngassapa, Thawatchai Santisuk, Vichai Reutrakul, Anne Howe, Marcia Moss, Jeffrey M. Besterman, Shi Lin Yang, John E. Farthing, R. Murray Tait, Jane A. Lewis, Melanie J. O'Neill, Norman R. Farnsworth, Geoffrey A. Cordell, John M. Pezzuto, A. Douglas Kinghorn
• Other Authors: University of Illinois at Chicago
• Format: Article
• Published: 2018
• Subjects: Biochemistry, Genetics and Molecular Biology; Chemistry; Medicine; Pharmacology, Toxicology and Pharmaceutics
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/17540
• Institution: Mahidol University

Chloroform-soluble extracts of the stems and of the mixed stems and stem bark of Lophopetalum wallichii were found to be inhibitory in a farnesyl protein transferase (FPTase) bioassay system. During the course of activity- guided fractionation, the known lupane-type triterpenes, ochraceolide A (1), ochraceolide B (2), betulin, and lupeol and the new lupane lactone, dihydro ochraceolide A (4), were isolated. The stereochemistry of the epoxide group of ochraceolide B (2) was determined by preparation of both epoxide isomers [2, and the new semisynthetic derivative, 20-epi-ochraceolide B (3)] from 1. The structure of 4 was established by reduction of 1 with sodium borohydride. Compounds 1 and 2 exhibited significant inhibitory activity in the FPTase assay (IC50values of 1.0 and 0.7 μg/mL, respectively). Lupeol was found to be weakly active (IC5065.0 μg/mL) in this test system, whereas no significant inhibition was detected for betulin or compounds 3 or 4. When evaluated against a panel of human cancer cells in culture, compounds 1 and 4 were modestly cytotoxic. Compounds 2 and 3 were not active in the panel.